1-{8 3-(1-ethynlcyclohexyloxy)-2-hydroxy{9 -propyl-{8 4-phenyl, or 4-(2-phenyl-2-alkoxy)-{9 ethyl-piperzines

ABSTRACT

IN WHICH R is an alkyl group having 1 to 4 carbon atoms, and salts thereof with acids. The compounds are of use in therapeutics, particularly in view of their effect on the central nervous system, their hypotensive effect, their anti-emetic effect, and their antitussive effect. A new group of N-substituted piperazines are disclosed having the formula:   IN WHICH R1 and R2 are like or unlike alkyl groups having 1 to 4 carbon atoms or R1 and R2 taken together with the carbon atom to which they are attached form a cycloalkyl group having 5 to 8 carbon atoms and Y is either (a) a group having the formula   D R A W I N G IN WHICH X is hydrogen or halogen atom, a trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, or (b) a group having the formula

Muted States Patent r 1 Mauvernay et al.

[111 3,884,923 [45] May 20, 1975 1-[3-(l-ETHYNLCYCLOHEXYLOXY)-2- HYDROXY]-PROPYL-[4PHENYL, OR 4-( Z-PHENYL-Z-ALKOXY METHYL- PIPERZINES [22] Filed: Apr. 12, 1973 [21] Appl. No.: 350,517

[30] Foreign Application Priority Data Apr. 13, 1972 France 72.12893 [52] US. Cl. 260/268 PH; 260/268 R; 424/250 [51] Int. Cl C07d 51/70 [58] Field of Search 260/268 R, 268 H, 268 N,

' 260/563 R, 563 C, 268 PH [56] References Cited UNITED STATES PATENTS 3,170,926 2/1965 Ash et a1. 260/268 PH 3,723,476 3/1973 Nakanishi et al. 260/268 R Primary Examiner-Donald G. Daus Assistant Examiner-Jose Tovar [57] ABSTRACT A new group of N-substituted piperazines are disclosed having the formula:

R C ECH R 0 -CH -CIIH-CH N in which R and R are like or unlike alkyl groups having 1 to 4 carbon atoms or R and R taken together with the carbon atom to which they are attached form a cycloalkyl group having 5 to 8 carbon atoms and Y is either (a) a group having the fonnula in which X is hydrogen or halogen atom, a trifluoromethyl group, an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, or (b) a group having the formula in which R is an alkyl group having 1 to 4 carbon atoms, and salts thereof with acids. The compounds are of use in therapeutics, particularly in view of their effect on the central nervous system, their hypotensive effect, their anti-emetic effect, and their antitussive effect.

7 Claims, No Drawings 1-[3-(1-ETHYNLCYCLOHEXYLOXY)-2- HYDROXY]-PROPYL-[4-PHENYL, OR R 4-(2-PHENYL-2-ALKOXY)-]ETHYL-PIPERZINES FR o CH CH 2 I This invention relates to anew group of N-,5 2 (H) substituted piperazines-defmed by the general formula:

in which R is an aryl group, which may be substituted,

, i c CH and may be 'a naphthyl group, and R R are hydrogen atomsoralkyl groups, have a controlling effect on the 1 C 7 l adrenergic B-receptors WlllCh is similar to that of epinephrine.

n Moreover, Belgian Pat. No.'735,543 (1971 discloses 0 E N the psychosedative properties exhibited by compounds OH (I) having the general formula:

R 0 c @m-cu-cn -u ufiom l g I o in which R, and R are like or unlike alkyl groups havin which R is fluorine or chlorine." ing 1 to 4 carbon atoms or R and R taken together It has now been discovered that the compounds havwith the carbon atom to which they are attached form ing the general formula I above possess the'property of a cycloalkyl group having 5 to 8 carbon atoms and Y being free from any B-effect which would block adrenis either (a) a group having the general formula alin release, whilst possessing a depressant effect upon the central nervous system. X I The invention therefore contemplates the application in human therapeutics, as medicaments, for afflictions of a psycholeptic nature, of compounds having the general formula 1 above, and more especially those comin which X is a hydrogen halogen atom, a t ifl pounds in which the substituent Y is a'sdefined under ni e thyl'gro'up, an alkyl group having 1 to 4 carbon atoms oran alkoxy group having 1 to 4 carbon atoms, It has also been founfl compounds P g f or (b) a group having the general formula the same group have significant hypotensive and antiemetic properties.

Finally, it has also been found that compounds having the general formula I above, and especially those in 2 which the substituent Y is as defined under (b), have 0R a marked antitussive effect which is of the order of five 40 times greater than that of a known, non-opiate antitusin which R is an alkyl group having 1 to 4 carbon sive agent, namely pentoxyverine. The invention thereatoms, and salts thereof with acids. 1 fore also relates to this other application of the com- The compounds are of use in therapeutics, particupounds in human therapeutics. larly in view of their effect on the central nervous sys- Finally, the invention also relates to a process for pretem, their hypotensive effect, their antiemetic effect, paring the compounds having the general formula I, and their antitussive effect. which process comprises two stages;

The invention also relates to the production of these In the first stage, an acetylenicalcohol is reacted with compounds and to their pharmaceutically acceptable epichlorohydrin in the presence of boron fluoride (ethsalts, such as the dihydrochlorides. erate), and in the second stage, the intermediate chlo- Previous studies, among which may be cited: A. Burrohydrin thus obtained, which may first be converted ger, Medicinal Chemistry, .I. Wiley, 1970, page 1053 into an epoxide, is reacted with an N-substituted piperand J. W. Black et al., The Lancet" Volume 1 1964, azine carrying the substituent Y. page 1080, have shown that aminopropanediol deriva This process may be illustrated by the following flow tives having the general formula: diagram:

OH o EXAMPLE 1 The preparation of l-3-(1ethynyl)cyclohexyloxy-2- hydroxy propyl-4-(4-fluorophenyl)piperazine. (Compound No. 4).

. First stage 92.5 g (1M) of epichlorohydrin are progressively added to 186g of ethynylcyclohexanol (A) to which has been added 1 ml of a of boron trifluoride in di- 108g (0.5M) of the product of the first stage (B), and 59g (0.33M) of parafluorophenylpiperazine dissolved in 350 ml of n-butanol are heated to reflux in the presence of 42g of sodium bicarbonate while stirring for 20 hours. After the precipitate which forms has been removed, the solution is concentrated to 50 and the product crystallises on cooling. After recrystallisation from ethanol, 88g of product are obtained in the form of the base, m.pt 106C.

The dihydrochloride is prepared by dissolving the base in 96 ethanol and adding the exact quantity of hydrochloric acid required to a titrated solution in absolute ethanol, m.pt 183C.

EXAMPLE 2 A modification of the second stage of Example 1. In accordance with another embodiment of the invention, the chlorohydrin obt:ined in the previous stage may first be converted into an epoxide, the epoxy ring then being opened by the N-substituted piperazine.

ECH

A solution of 100g of soda in 100 cc of water is added to 100g of the chlorohydrin obtained in the first stage of Example l whilst cooling. The mixture is allowed to ethyl ether, while the temperature is maintained at return to ambient temperature and to react for 4 or 5 55C. Heating is then continued at C for one hours. After filtering, the organic phase is extracted hour, the mixture left to stand overnight, 10 ml of water with diethyl ether, dried over anhydrous sodium suladded and the product then distilled under reduced phate and the product is then separated by distillation pressure. g of product (B) are obtained, b.pt under reduced pressure after the solvent has been re- 107c/0.5 mm., n 1.4972 50 Second stage C CH C E CH GX UG- O-CH2-CH-CH2 c1 0H H ON-@-F CECH 0.1M (i.e. 18g) of this epoxide are then reacted with 0.1M (i.e. 18g) of parafluorophenylpiperazine by heating together under reflux for 2 hours in 50 cc of absolute alcohol. After the absolute alcohol has been evaporated, the base crystallises. After recrystallisation from absolute alcohol, 15.3g of product are obtained having a melting point of l06C.

EXAMPLE 3 The preparation of 1- 3-( l-methyllethynyl)propoxy-Z-hydroxy propyl-4-(2-ethoxy-2- phenyl)ethylpiperazine (Compound No. 25)

Under similar conditions to those set out in Example 1, there is obtained in the first stage, using as starting v 6 materials 118g of methylethylethynylcarbinol and 74g of cpichlorohydrin, 65g of the corresponding chlorohyr drin which was used in the second stage, b.pt

m o CH -lCHCH -N Q7 I 80C/0.5. mm., n 1.4627.

g" of the substituted piperazine prepared as describedinFrench Pat. No. 5.390 M, is then reacted to obtain 91 g of the desired product. The dihydrochloride has m.pt 211.5C.

' EXAMPLE 4 mam I R 0 CH c CH '|\C (CH /-\c 1 12 -CH2' -C -N N-Y or V O-C -CHCH-N N-Y i 0H 1 OH i impound No. 11 R1 R2 Y Di-X-lvircchleride Elementar Annl'rsis M 11.1% (c) ce 1 Theory Found Theory F ound Theory Found 1 5 0 11 011 0 389.38 179 58.60 5 .25 7.77 7.85 7 20 7.2-? 5 O 35. 1 185 58.2 59.09 7.20 7.45 6 6 6.5 5 ca {)3} 0-; 5 169 54.96 5;.97 6.92 7.2.2 '7. 1?. 7.00

. 6.6 1 6.7 6.83 7 6.90 7 011 c11 O +o9.80 168 52 52 8 J 8 5 On 9-87 56.06 56.70 6.95 7.05 6.23 6.21 9 C285 ciz 0-; 407.57 172 56.01 55.9 1 7.18 7.17 6.88' 6 55 1o 0 11 on 0-H 625.85 171 55.8 1 53.60 6.89 7.22 6.61 6.63

OCH 18 11 11 ca u19. i1 169.6 57.27 56.56 7.69 7. 19 6.6a- 6.63

OCH 1 1 ca on. Q 1 #0558 1 7.7 56.29 56.5'+ 7. 6 7. 18 6-9! 5 -'-CH -CH +715 213 60.87 5,0.

TABLE I (Cont.)

I l Compound No.5 n R1 Y Di-llydrochloritif Elementary Analysis 1 M 11.1% c ca, 150

I Theory Found Theory i e-12: 2 Theory FC'lIQl 2 22 5 c 2..|c|- 187.52 211 61.59 60.17 8.27 7.75 5.7% 5.71

. oc u OCH 2 1 (:1 011 -CH -FH 4 17.46 216 59.05 58 85 8.11 3 17 6.2- 6 :5

OC l-l 25 ca c 11 -CH CH- '61.- 21" 5 59.86 53 c7 1.) 3o 2 c1 OC l-l Compound No. n R R2 1' Di-I-lvdrochloride lament-arr Analysis 1 l-Z- 142+. (c) 591, theory I 22c". fouzd CF 162 1 6 16.0. 12 0 11 011 +5? 39 5 9 CF 13 011 011 443.36 166.5 16.46 16.

16 cit H 105.58 193.5 18.00 18.04

17 0 11 on OCH 589.58 190 18.75 12.66

The pharmacological properties of the members of this group of substances were tested as follows, results being reported only for those members most representative of the effect concerned.

EFFECT ON THE CENTRAL NERVOUS SYSTEM This effect was observed by means of a set of tests of which the most significant are summarised below: 1. Acute toxicity LD Oral administration This was determined upon the mouse by oral administration, the LD value being calculated by the method of B. Behrens & C. Karber (Arch F. Exp. Patho. Pharm., volume 177, page 379 (1935)) 2. Spontaneous motility of mice The animals were placed in a circular corridor traversed by 6 infrared beams which enable their movements to be counted. One batch of animals was used as a control. Motility is measured 10 minutes after administration by the oral method. 3. Potentiation of an inactive dose of a barbiturate The ED value gives the dose which, after an inactive dose of mebubarbital has been administered,

causes sleep to occur in 50 percent of the animals 15 minutes after the product has been administered.

4. Cataleptic effect This is determined on the rat by the homolateral crossed pawsmethod as described by J. R. Boissier and P. Simon, Therapie, volume 18, 1963, pages 1257-1277. 5. Group amphetamine toxicity This is determined on the mouse in accordance with the procedure described in Med. Pharmacol. Exp. Vol. 14, pages 435-442 (1966). 6. Electrical conflict in the mouse The test employed is that described by Tedeshi et al.,

0 Pharmacol. Exp. Thera. Vol. 125, page 28.

7. Biochemical dopamine effect on the brain This effect is measured by spectrofluorometric means using the Jobin-Yvon Beam apparatus, on the brains of mice of the strain OF 8. Anti-apomorphic effect in the rat This effect was demonstrated by the test of P. A. .lanssen, C. Niemegeers and A. H. M. Jagenau (see 9 Arzneimittelforschung, Vol.00, page ,l 3 ,(l960) i using an apomorphinedose of 0.6 mg/kg body-weight. Table 11 below also shows the results obtained with haloperidol which is a conventionahreference sub- Compounds 18 and 20 would appear active in apomorphine stereotypes, non-inducive of catalepsy and non-sedative, compound No. 20 being especially hypostance for psycholeptic agents. t'ensive.

TABLE II Com- Test No. 1 Test Test No. 3 7 Test No. 4 Test No. 5 Test No. 6 Test No. 7 Test N 8 pound TOXICITY 2 CATALEPSY AMPHET- ELECT Rl- CEREBRAL ANTI-2P0- AMINE CAL No. LD MOTILITY CONFLICT DOPAMINE MORPHI CA. CA. O.A. l.P. l.P. GA. 1.1. NE

2 600 I0 I00 50 40 50 At 40mg/kg 50 Subcutan- -337 3 600 100 100 Inactive at 40 50 At 60mg/kg 6-0115 45% 4 800 2.5 20 20 10 30 At IOmg/kg 92 O.A.

507 8 600 I5 50 30 40 50 At 80 m g/kg 787. 9 600 100 100 60 50 At eomglk 507- l l 783 25 90 Inactive at 5 12.5 lnactiv e CA.

4 l8 200 Inactive Inactive at 5 At ZOrng/kg l0 Subcutan- 40 -24% eous 20 60 40 Inactive Inactive at 10 4O Inactive 5 LP.

20 Halo- 125 l 12 l 0.5 0.5 At lOmg/kg 0.5 Subcutanperidol eous O.A. Oral administration l.P, Intruperitonal administration It will also be noted that all these products exhibit analgesic properties in varying degrees. For the members of this group it appeared interesting to supplement the foregoing study by testing the effect on arterial bloodpressure.

EFFECT ON ARTERIAL BLOOD-PRESSURE This was measured on the dog anaesthetised with chloralose by recording both the extent of, and the duration of, the effect on carotid arterial blood-pressure.

The product under study was administered intravenously in the doses shown in Table 111.

These initial experimental results show that the members of this group of chemical products have a spectrum of pharmacological activity of the psycholeptic type, and more specifically, of the neuroleptic type.

Nevertheless, in contrast to what is normally found 60 Compound No. 3 appeared to be only slightly neuroleptic but markedly hypotensive.

ANTI-EMETIC EFFECT The anti-emetic effect, which may constitute a contributory factor to the main effect, was also systematically tested in accordance with the following procedure:

Dogs of the beagle breed were split up at random into groups of 3 animals. After fasting for 24 hours, the animals were given an empty capsule then, one hour later, received a sub-cutaneous injection of apomorphine hydrochloride (0.3 mg/kg). The number of attempted vomits during minutes was then counted.

After 15 days rest, the same animals were given a capsule identical to that given on the first occasion but containing the product to be tested. The injection of apomorphine was carried out under the same conditions as for the control experiment.

Table IV summarises the results obtained in comparison with metoclopramide, which is a powerful and widely used anti-emetic.

TABLE IV Compound No. Doses Method of Reduction in (mg/kg) administration attempted vomits 4 l Subcutaneous 74 8 5 Oral 76 l 1 10 Oral 20 l Subcutaneous I00 1 Oral I00 Metoclopramide I Subcutaneous I00 1.5 Oral with known neuroleptic groups, i.e., phenothiazines and butyrophenones, there is, in the group in question, a marked dissociation between the various properties, which constitutes the feature of interest in this group. I Thus, Compound No. 4 shows afairly full spectrum characteristic of neuroleptic activitywi th the principal feature being a depletion of cerebralmono-amines in a manner reminiscent of reserpine. Compound No. l l is extremely active in apomorphine stereotypes, slightly All these compounds exert a powerful anti-emetic ef- 65 feet. The inhibition in the emetic effect of apomorphine on the dog is particularly evident in the case of compound No. 20 since it is equal to that of metoclopramide after subcutaneous injection, and superior to that of metoclopramide after oral administration.

ANTITUSSIVE EFFECT Finally, the compounds of the invention having shown themselves to be powerful antitussive agents, the results of comparative tests for this activity on four compounds of the invention and on pentoxyverine, one of the most powerful antitussive agents at present known, are given below in Table V.

The technique used was the method of R. Domenjoz. Arch. Exp. Pathol. V. Pharmacol. Volume 215, page 19 (1952) The cat is anaesthetized with ether and tracheotomised.

Coughing spasms are induced by stimulating a laryngeal nerve. After the product to be tested has been administered, fresh stimulation enables the inhibition achieved and its duration to be assessed.

These results show a clear antitussive activity, the two most interesting compounds being numbers 22 and 25. In comparison with a non-opiate antitussive agent, namely pentoxyverine, it can be seen that it is necessary to use doses five times greater than those used in the case of these two compounds to achieve a comparable effect.

It is therefore possible to envisage the use of these products in human therapeutics for their effect upon the central nervous system, and also as anti-emetic and antitussive agents, in daily doses of to 50 mg. These doses may be increased to 100 mg if a hypotensive action is sought. The products may be administered in the normal pharmaceutical forms, using conventional pharmaceutically acceptable diluents.

The examples given below are illustrations only of forms suitable for administration. 30mg tablets The unit formula for finished tablets having a weight of 115 mg is as follows:

Compound No. 20 mg Lactose 30 mg Microcrystalline cellulose 50 mg Starch 20 mg Polyethylene glycol 6000 1 mg Magnesium stearate 4 mg The lactose, the cellulose, and a pre-sieved portion of the starch are placed in a planetary mixer. After Compound No. 20 has been added in portions, the mixture is wetted with a 10% starch paste and then granulated; after drying, the polyethylene glycol 6000 and the magnesium stearate are added and the resulting mass compressed.

Injectable 5mg ampoules Compound No. 4 is dissolved in the usual way to produce an isotonic solution having a pH of 4 to 5. The solution is then used to fill into 2 ml ampoules.

Syrups containing 0.5 mg/ml The unit formula for this preparation is as follows:

Compound No. 25 50 mg 5 Sugar 8] g POBM 50 mg Flavour/colouring After the sugar and Compound No. 25 have been separately dissolved, the two solutions are mixed while 10 the POBM, the flavour, and the colouring are added and the mixture is supplemented by the appropriate amount of water to make up the unit formula. After stirring and homogenisation the resulting syrup is filtered and bottled.

What we claim is:

l. A piperazine of the formula C ECH wherein Y is selected from the group consisting of groups having the formula wherein X is selected from the group consisting of hydrogen, halogen, trifluoromethyl, alkyl of l-4 carbon atoms, and alkoxy of l-4 carbon atoms, and groups having the formula wherein R is alkyl of l-4 carbon atoms, or the pharmaceutically acceptable acid addition salts thereof.

2. A piperazine according to claim 1 wherein Y is a group having the formula 

1. A PIPERIAZINE OF THE FORMULA
 2. A piperazine according to claim 1 wherein Y is a group having the formula
 3. 1-(3-(1-ethynylcyclohexyloxy)-2-hydroxy)-propyl-4-(4-fluorophenyl)piperazine or the dihydrochloride thereof.
 4. 1-(3-(1-ethynylcyclohexyloxy)-2-hydroxy)-propyl-4-(4-chlorophenyl)piperazine or the dihydrochloride thereof.
 5. 1-(3-(1-ethynylcyclohexyloxy)-2-hydroxy)-propyl-4-(3 -trifluoromethylphenyl)piperazine or the dihydrochloride thereof.
 6. 1-(3-(1-ethynylcyclohexyloxy)-2-hydroxy)-propyl-4-(2 -methoxyphenyl)piperazine or the dihydrochloride thereof. k
 7. 1-(3-(1-ethynylcyclohexyloxy)-2-hydroxy-)propyl-4-(2-ethoxy-2 -phenyl)ethylpiperazine or the dihydrochloride thereof. 